Because major depression is associated with an increased incidence of thrombembolic disease, we are measuring laboratory parameters of coagulation and fibrinolysis in cohorts of depressed patients and control subjects. There are two study groups: (1) individuals under long-term observation are being tested in the morning and evening to assess possible perturbations in the natural diurnal variation of factor VIII and plasminogen activator inhibitor-1 (PAI-1); (2) individuals being infused with insulin and glucose to assess their insulin resistance are being tested before and after the infusions with measurements of factor VIII, thrombin-antithrombin complexes, and PAI-1. Results: the diurnal variation of factor VIII appears to be blunted in depressed patients, with factor VIII remaining higher throughout the day. Approximately a quarter of the depressed individuals have significantly elevated PAI-1 both in the morning and evening. Insulin infusion increases factor VIII activity (but not antigen level) and thrombin production (thrombin-antithrombin complexes), and lowers PAI-1 (presumably by increasing the production of tPA), significantly more in depressed patients than in control subjects. Conclusions: the increased incidence of thromboembolic disease in patients with major depression may be mediated by underlying hypercoagulability.